To determine the efficacy of phosphate replacement in the therapy for diabetic ketoacidosis (DKA), 44 patients were randomly assigned to three treatment groups: those who received no phosphate replacement, those who received 15 mmole of sodium phosphate at the fourth hour, or those who received 15 mmole of sodium phosphate at 2, 6, and 10 hours. All patients were treated with intravenous insulin injection (0.1 units/kg/hr), fluids, and potassium. Four hours after a 15-mmole sodium phosphate infusion, the serum phosphate level was 2.8 +/- 0.8 mg/dL vs 2.1 +/- 0.8 mg/dL in the control patients; however, this dose was insufficient to maintain the serum phosphate level at 16 and 24 hours. Forty-five millimoles of phosphate prevented severe hypophosphatemia in all but one patient and produced substantially higher phosphate levels at 8, 16, and 24 hours. Phosphate therapy did not affect the duration of DKA, dose of insulin required to correct the acidosis, abnormal muscle enzyme levels, glucose disappearance, or morbidity and mortality. Although theoretically appealing, phosphate therapy is not an essential part of the therapy for DKA in most patients.